Patients with cancer have multiple symptoms, such as pain, fatigue, sleep disturbance, and poor appetite that cause significant distress, impair function and rehabilitation, and may cause treatment delays or premature treatment termination. These symptoms are caused by both the cancer and its therapy. When the cancer is incurable, as is multiple myeloma (MM), the balance between the side effects of aggressive treatment and optimal function becomes critical. There is growing evidence that some of these symptoms may cluster together and share common physiologic mechanisms, creating a "symptom burden" that is the subjective counterpart of tumor burden. The recent evolution of the animal "sickness behavior" model which is strikingly similar to symptoms reported by cancer patients undergoing treatment (Cleeland et al., 2003;Lee et al., 2004, Dantzer &Kelley, 2007), presents an exciting opportunity I) to test for possible physiologic mechanisms of symptom production, and 2) to examine new strategies to reduce or prevent cancer-related symptoms. The overall hypothesis to be tested in this program project is that increases in specific proinflammatory cytokines, especially IL-I, IL-6 and TNF-a, and activation of their precursor, NF-kb, are associated with the emergence of individual symptoms or clusters of treatment-related symptoms, and that modulation of these inflammatory pathways will reduce both the prevalence and severity of symptoms. Preliminary data presented for this program are supportive of this hypothesis. A project of this nature necessitates a broadly based integrated and multidisciplinary Program Project that includes expertise in longitudinal symptom assessment, immunology, quantative motor and sensory assessment, and animal models of symptoms and disease where mechanisms of symptom expression can be examined. A special requirement is for the development of statistical models that can account for the relationship of symptom and biological variables over time. Components of the individual projects will follow MM patients from diagnosis through induction therapy, transplantation, and maintenance therapy. MM presents an ideal disease to test these hypotheses, since proinflammatory cytokines play a major role in the development of the disease, aggressive treatments exacerbate production of proinflammatory cytokines and, in recent years, there has been an increase in knowledge about and availability of agents for inflammatory blockade that make mechanistic symptom control a real possibility in the trajectory of this disease. Our long-term objective is to create a foundation for a mechanism-driven symptom control strategy for managing disease and treatment-related symptoms. Having the ability to reduce symptom burden or even prevent these consequences from therapy would be of potential benefit to thousands of cancer patients and survivors by improving the tolerability of treatment and reducing posttreatment residual symptoms.